Medical Pharmacology: Antiarrhythmic Drug Classes

Chapter 8 Medical Pharmacology: Antiarrhythmic Agents

Class I: Sodium Channel Blockers
- Sodium channel blocking antiarrhythmic drugs are classified as use-dependent in that they bind to open sodium channels.
  - Their effectiveness is therefore dependent upon the frequency of channel opening.
There are three classes or types of sodium channel blockers:
- Type Ia: prototype: quinidine gluconate (Quinaglute, Quinalan). Type Ia drugs slow the rate of AP rise and prolong ventricular effective refractory period.
- Quinidine
  - Overview
    - Dextroisomer of quinine; quinidine gluconate (Quinaglute, Quinalan) also has antimalarial and antipyretic effects
    - Pharmacokinetics:
    - 80%-90%: bound to plasma albumin
    - Rapid oral absorption; rapid attainment of peak blood levels (60-90 minutes)
    - Elimination half-life: 5-12 hours
    - IM injection, possible but not recommended due to injection site discomfort
    - IV administration: limited due to myocardial depression and peripheral vasodilation
  - Metabolism:
    - Hepatic: hydroxylation to inactive metabolites; followed by renal excretion
    - 20% excreted unchanged in urine
      - Impaired hepatic/renal function: accumulation of quinidine and metabolites
    - Sensitive to enzyme induction by other agents, e.g.
      - Decreased quinidine blood levels with phenytoin, phenobarbital, rifampin
  - Mechanism of antiarrhythmic action-- primarily activated sodium channel blockade which results in:
    - Depression of ectopic pacemaker activity
    - Depression of conduction velocity
      - May convert a one-way conduction blockade to a two-way (bidirectional) block -- terminating reentry arrhythmias
    - Depression of excitability (particularly in partially depolarized tissue)
    - Recovery from sodium channel blockade is slower in depolarized tissue (compared to normal tissue):
      - This is the basis for relative selectivity of quinidine action in depolarized tissue compared to normal tissue, (i.e. lengthened refractory period, depressed conduction velocity, reduced excitability observed in depolarized tissue to greater extent the normal tissue)
    - Although classified as a sodium channel blocker, quinidine also blocks K+ channels.
      - Most antiarrhythmic agents have such multiple actions.
  - Effect on the ECG: QT interval lengthening
    - Basis: quinidine-mediated reduction in repolarizing outward potassium current
      - Result:
        
        Longer action potential duration
        
        Increased effective refractory period
        
        Reduces reentry frequency; reduced rate in tachyarrhythmias
  - Sodium channel blockade results in:
    - An increased threshold
    - Decreased automaticity.
  - Quinidine Uses
    - Used to manage nearly every form of arrhythmia especially acute and chronic supraventricular dysrhythmias
    - Ventricular tachycardia
    - Frequent indications:
    - Prevent recurrence of supraventricular tachyarrhythmias
    - Suppression ventricular premature contractions
    - Approximately 20% of patients with atrial fibrillation will convert to normal sinus rhythm following quinidine treatment Supraventricular tachyarrhythmia due to Wolff-Parkinson-White syndrome -- effective suppression by quinidine
    - Digitalization prior to quinidine administration:
    - Quinidine sulfate (Quinidex,Quinora)/quinidine gluconate (Quinaglute, Quinalan) may cause a paradoxical increase in ventricular response due to quinidine's vagolytic effect at the AV node
      - Quinidine's antimuscarinic action increases AV nodal throughput, allowing more SA nodal impulses to reach the ventricle.
    - Vagotonic effects on digitalis prevents this paradoxical increase by increasing vagal tone at AV node
    - Quinidine sulfate (Quinidex,Quinora) administration results in vagal inhibition (anti-muscarinic) and alpha-adrenergic receptor blockade.
  - Quinidine Side Effects
    - Cardiovascular--at (high) plasma concentrations (> 2ug/ml)
      - Prolongation (ECG) of PR interval, QRS complex, QT interval
      - Heart block likely with 50% increase in QRS complex duration (reduced dosage)
        
        Quinidine syncope: may be caused by delayed intraventricular conduction, resulting in ventricular dysrhythmia
        
        Patients with preexisting QT interval prolongation or evidence of existing A-V block (ECG): probably should not be treated with quinidine
      - Hypotension -- primarily following IV administration
        
        Mechanism: peripheral vasodilation secondary to alpha-adrenergic receptor blockade
        
        Increased hypotension risk associated with quinidine +verapamil treatment
      - Effects on heart rate:
        
        Increase secondary to either quinidine's antimuscarinic effect and/or reflex increase in sympathetic activity
      - Quinidine is associated with Torsades de pointes, a ventricular arrhythmias associated with marked QT prolongation.
        
        Torsades de pointes

Torsades de pointes: Electrophysiological Features

Ventricular origin

Wide QRS complexes with multiple morphologies

Changing R - R intervals

Axis seems to twist about the isoelectric line

This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level.

Other quinidine adverse effects include:

Cinchonism

Blurred vision, decreased hearing acuity, gastrointestinal upset,headaches and tinnitus.

Nausea, vomiting, diarrhea (30% frequency)

Drug-drug interaction:quinidine gluconate (Quinaglute, Quinalan)-digoxin (Lanoxin, Lanoxicaps)

Quinidine increases digoxin plasma concentration; may cause digitalis toxicity in patients taking digoxin or digitoxin

Effects on neuromuscular transmission:

Quinidine gluconate (Quinaglute, Quinalan) interferes with normal neuromuscular transmission; enhancing the effect of neuromuscular-blocking drugs

Recurrence of skeletal muscle paralysis postoperatively may be associated with quinidine administration

Procainamide
- Overview:
  - Local anesthetic (procaine) analog
  - Long-term use avoided because of lupus-related side effect
- Metabolism:
  - Elimination: renal excretion and hepatic metabolism; by contrast to procaine, procainamide is highly resistant to hydrolysis by plasma esterases.
  - 40%-60% excreted unchanged (renal)
  - Renal dysfunction requires procainamide dosage reduction
  - Hepatic metabolism -- acetylation
    - Cardioactive metabolite: N-acetylprocainamide (NAPA);
      - NAPA accumulation may lead to Torsades de pointes
    - Quinidine and Procainamide similar: electrophysiological properties.
    - Possibly somewhat less effective in suppressing automaticity; possibly more effective in sodium channel blockade in depolarized cells
    - Useful in acute management of supraventricular and ventricular arrhythmias.
      - Drug of second choice for management of sustained ventricular arrhythmias (in the acute myocardial infarction setting)
      - Effective in suppression of premature ventricular contractions and paroxysmal ventricular tachycardia rapidly following IV administration
    - Most important difference compared quinidine: procainamide does not exhibit vagolytic (antimuscarinic) activity.
    - Procainamide is less likely to produce hypotension, unless following rapid IV infusion
    - Ganglionic-Blocking Activity
- Side Effects/Toxicities
  - Long term use is associated with side effects, including a drug-induced, reversible lupus erythematosus-like syndrome which occurs at a frequency of 25% to 50%.
    - Consists of serositis, arthralgia and arthritis
    - Occasionally: pluritis, pericarditis, parenchymal pulmonary disease
    - Rare: renal lupus
    - Vasculitis not typically present (unlike systemic lupus erythematosus)
    - Positive antinuclear antibody test is common; symptoms disappear upon drug discontinuation
    - In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and earlier in therapy than in rapid acetylators.
  - Nausea, Vomiting -- most common early, noncardiac complication

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Disopyramide (Norpace)
- Overview:
  - Very similar to quinidine gluconate (Quinaglute, Quinalan)
  - Greater antimuscarinic effects (in management of atrial flutter and fibrillation, pre-treatment with a drug that reduces AV conduction velocity is required)
  - Approved use (USA): ventricular arrhythmias
- Metabolism:
  - Dealkylated metabolite (hepatic); less anticholinergic, less antiarrhythmic effect compared apparent compound
  - 50% excreted unchanged, renal
- Electrophysiological effects similar to quinidine gluconate (Quinaglute, Quinalan)
  - Similar to quinidine gluconate (Quinaglute, Quinalan) in effective ventricular and atrial tachyarrhythmia suppression
  - Prescribed to maintain normal sinus rhythm in patients prone to atrial fibrillation and flutter and is also used to prevent ventricular fibrillation or tachycardia.
- Side Effects/Toxicity
  - Adverse side-effect profile: different from qunidine's in that disopyramide (Norpace) is not an alpha-adrenergic receptor blocker but is anti-vagal.
  - Most common side effects: (anticholinergic)
    - Dry mouth
    - Urinary hesitancy
  - Other side effects: blurred vision, nausea
  - Cardiovascular:
    - QT interval prolongation (ECG)
    - Paradoxical ventricular tachycardia (quinidine-like)
  - Negative inotropism (significant myocardial depressive effects)--undesirable with preexisting left ventricular dysfunction (may promote congestive heart failure, even in patients with no prior evidence of myocardial dysfunction)
    - Disopyramide is not a first-line antiarrhythmic agent because of its negative inotropic effects
    - If used, great caution must be exercised in patients with congestive heart failure
  - Can cause torsades de pointes, a ventricular arrhythmia

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241;Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Type Ib
- Class Ib agents are often effective in treating ventricular arrhythmias. Example: lidocaine. Type Ib agents exhibit rapid association and dissociation from the channel.
- Mexiletine (Mexitil) (Class IB, Sodium Channel Blocker)
  - Overview
    - Amine analog of lidocaine (Xylocaine), but with reduced first-pass metabolism.
    - Suitable for oral administration
    - Similar electrophysiologically to lidocaine
  - Clinical Use:
    - Chronic suppression of ventricular tachyarrhythmias
    - Combination with a beta adrenergic receptor blocker or another antiarrhythmic drug (e.g. quinidine gluconate (Quinaglute, Quinalan) or procainamide (Procan SR, Pronestyl-SR)): synergistic effects allow:
      - Reduced mexiletine dosage
      - Decreased side effect incidence
    - Possibly effective: decreasing neuropathic pain when alternative medications have proven ineffective-- applications (on-label use):
      - Diabetic neuropathy
      - Nerve injury
  - Side effects:
    - Epigastric burning: usually relieved by a taking drug with food
    - Nausea (common)
    - Neurologic side effects:
      - Diplopia, vertigo, slurred speech (occasionally), tremor
- Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker)
  - Overview/Pharmacokinetics:
    - Local anesthetic administered by i.v. for therapy of ventricular arrhythmias
    - Extensive first-pass effect requires IV administration
    - Half-life: two hours
    - Infusion rate: should be adjusted based on lidocaine plasma levels
    - Factors influencing loading and maintenance doses:
      - Congestive heart failure (decreasing volume of distribution and total body clearance)
      - Liver disease: plasma clearance -- reduced; volume of distribution -- increased; elimination half-life substantially increased (3 X or more)
      - Drugs that decrease liver blood flow (e.g. cimetadine, propranolol), decreased lidocaine clearance (increased possible toxicity)
  - Metabolism
    - Hepatic: some active metabolites
  - Cardiovascular Effects:
    - Site of Action: Sodium Channels
      - Blocks activated and inactivated sodium channels (quinidine blocks sodium channels only in the activated state)
      - During diastole, in normal tissue, as membrane potential returns to normal resting levels (-90 mV) lidocaine rapidly dissociates from the channel (low affinity for the channel resting state)
      - During diastole, in ischemic tissue, the membrane potential does not return to normal resting levels but remains partially depolarized and lidocaine remains bound (higher affinity, longer time constant for unblocking that at less negative resting potentials)
      - Therefore, lidocaine is more effective in suppressing activity in depolarized, arrhythmogenic cardiac tissue but has little effect on normal cardiac tissue -- the basis for this drug's selectivity.
        
        Very effective antiarrhythmic agent for arrhythmia suppression associated with depolarization (e.g., digitalis toxicity or ischemia)
        
        Comparatively ineffective in treating arrhythmias occurring in normally polarized issue (e.g., atrial fibrillation or atrial flutter)
      - No significant effect on QRS or QT interval or on AV conduction (normal doses)
      - Lidocaine (Xylocaine) decreases automaticity by reducing the phase 4 slope and by increasing threshold.
    - Clinical Uses:
      - Suppression of ventricular arrhythmias (limited effect on supraventricular tachyarrhythmias)
      - Suppression of reentry-type rhythm disorders:
        
        Premature ventricular contractions (PVCs)
        
        Ventricular tachycardia
      - May reduce incidence of ventricular fibrillation during the initial time frame following acute myocardial infarction; no evidence to support prophylactic use and myocardial infarction
    - Side Effect/Toxicities
      - Overdosage:
        
        Vasodilation
        
        Direct cardiac depression
        
        Decreased cardiac conduction -- bradycardia; prolonged PR interval; widening QRS on ECG
      - Major side effect -- neurological
        
        Large doses, rapidly administered can result in seizure.
        
        Factors that reduce seizure threshold for lidocaine:
        
        Hypoxemia, hyperkalemia, acidosis
        
        Otherwise: CNS depression, apnea.
- Tocainide (Class I, Sodium Channel Blocker)
  - Amine analog of lidocaine, similar to mexiletine, orally active --but with reduced first-pass metabolism.
  - Used for chronic suppression of ventricular tachyarrhythmias
  - Electrophysiologically similar to lidocaine
  - Similar to mexiletine: tocainide + if beta-adrenergic receptor blocker or another antiarrhythmic drug: synergism
    - e.g. Combination with quinidine may increase efficacy and diminish adverse effects.
  - Side Effects:
    - Profile similar to mexiletine
    - Suitable for oral administration, but RARELY USED due to possibly fatal bone marrow aplasia and pulmonary fibrosis.
    - Tremor and nausea are major dose-related adverse side effects
  - Excreted by the kidney, accordingly dose should be reduced in patients with renal disease

Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Phenytoin

Overview

Effective in suppression of ventricular arrhythmias associated with digitalis toxicity

Less effective than quinidine, procainamide, or lidocaine, in treatment of ventricular arrhythmias due to other etiologies

Pharmacokinetics:

Routes of administration: oral, or IV

Normal saline preferred -- phenytoin may precipitate in 5% dextrose in water

Slow IV injection into large peripheral or central vein preferable-- decreased chance of:

Discomfort

Thrombosis at injection site

Hepatic Metabolism --hydroxylation and conjugation (glucuronidation):

Elimination half-life: approximately 24 hours

Impaired hepatic function may cause excessive phenytoin blood levels

Mechanism of Action/Cardiac Effects:

Electrophysiological effects on automaticity and conduction velocity--somewhat like lidocaine

Shortens QT interval more than any other antiarrhythmic agent

No significant effect on ST-T waves or QRS complex

No significant myocardial depression

Improvement in AV Node Conduction;

Depression of SA Nodal Activity

Drug-Drug Interaction:

Significant SA nodal depression may occur when combining those volatile anesthetics that depress SA nodal activity and phenytoin

Drugs that lower phenytoin levels:

Barbiturates (mechanism:metabolizing enzyme induction)

Drugs that increase phenytoin level (inhibit metabolism):

Warfarin, phenylbutazone, isoniazid

Side effect/Toxicities:

Primary Toxicity: CNS disturbance (particularly cerebellar-- dose correlated > 18 ug/ml-- exceeding this concentration is unlikely to improve cardiac rhythm)

CNS symptoms:

Ataxia, vertigo, slurred speech, sedation, nystagmus, confusion

Partial inhibition of insulin secretion: enhances blood glucose levels in hyperglycemic patients

Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Type Ic: Type Ic drugs slowly dissociate from resting sodium channels

Flecainide (Tambocor)--( Na⁺ and K⁺ Channel Blocker)

Overview:

Fluorinated local anesthetic analog of procainamide (Procan SR, Pronestyl-SR)

More effective than quinidine gluconate (Quinaglute, Quinalan) or disopyramide (Norpace) in:

Suppressing ventricular tachycardia

Suppressing ventricular premature contractions

Pharmacokinetics:

Oral absorption: excellent

Long elimination half-time (approximately 20 hours)

25% flecainide: excreted unchanged (kidneys)

Hepatic metabolism: weakly active metabolites

Factors reducing flecainide elimination:

Congestive heart failure

Renal failure

Cardiac Effects/Clinical Use:

Suppression ventricular tachycardia and ventricular premature contractions

Effective in management of atrial tachyarrhythmias

Effective in tachyarrhythmias associated with Wolff-Parkinson-White syndrome (suppression of conduction bypass tracts)

Chronic flecainide (Tambocor) treatment following myocardial infarction not recommended:

Increased incidence of sudden death in treated patients

In CAST, flecainide increased mortality in patients recovering from myocardial infarction.

Flecainide: should be reserved for management of life-threatening arrhythmias

Slight/moderate negative inotropic property

Proarrhythmic effects in patients with preexisting left ventricular function deficiency

Electrophysiology:

Prolongation of PR interval (ECG)

Prolongation of QRS complex (> 25%)

Sinoatrial nodal depression (similar to beta-adrenergic blockers and calcium channel blockers)

Side-Effects/Toxicities

Most common:vertigo and difficulty in visual accommodation

Most serious of adverse effects is induction of potentially lethal arrhythmias such as reentrant ventricular tachyarrhythmias.

Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Amiodarone (Cordarone) (Class I and III Channel Blocker)

Overview:

A benzofurane derivative, 37% iodine by weight, structurally similar to thyroxine

May cause hypothyroidism or hyperthyroidism (frequency: 2%-4%)

Insidious development

Patients with previous thyroid dysfunction: more likely to develop amiodarone-mediated thyroid effects

Hyperthyroidism: most readily evidenced by increased plasma level of triiodothyronine

Secondary to iodine release from parent drugs;

Often refractory to conventional treatment

Intolerant of beta-adrenergic receptor blockade (because of underlying cardiac disease)

Following failed medical management: surgical thyroidectomy is appropriate

Bilateral superficial cervical plexus block has been used for anesthetic management of subtotal thyroidectomy in this patient group

Hypothyroidism: most readily evidenced by increased plasma level of thyroid-stimulating hormone (TSH)

May interfere with certain radiologic procedures (Iodine accumulation)

Approved for use only in treatment of serious ventricular arrhythmias (USA)

Also used for refractory supraventricular arrhythmias

Numerous adverse effects.

Metabolism and Excretion

Long elimination halftime: 29 days

Minimal renal excretion

Principal metabolite (desmethylamiodarone) -- longer elimination halftime compared to amiodarone

Extensive protein binding

Amiodarone concentrated in the myocardium (10-50 times plasma concentration)

Cardiovascular Properties and Uses:

Used in patients with ventricular tachycardia or fibrillation resistant to treatment with other drugs.

Effective inhibitor of abnormal automaticity.

Oral administration, preoperatively, reduces likelihood of atrial fibrillation following cardiac surgery.

Suppresses tachyarrhythmias associate with Wolff-Parkinson-White syndrome

secondary to depression of conduction in the AV node and accessory bypass tracts.

Similar to β-blockers (unlike most class I antiarrhythmics), amiodarone decreases mortality after myocardial infarction

Antiarrhythmic effectiveness begins within 72 hours following initiation of oral treatment; nearly immediate effect following IV administration

Following discontinuation of chronic oral therapy: pharmacological effects may last up to two months (long elimination half-time)

Mechanism of Action

Blocks sodium and potassium channels and prolongs action potential duration.

Prolongs effective refractory period in:

SA node

AV node

Ventricle

Atrium

His-Purkinje system

Accessory bypass tracts (Wolff-Parkinson-White syndrome)

Vascular Effects

Noncompetitive alpha and beta adrenergic receptor blocker

Systemic vasodilation

Antianginal properties, secondary to coronary vasodilation

Side Effects

Pulmonary:

Most serious adverse effect seen in long-term therapy is a rapidly progressive pulmonary fibrosis which may be fatal

Frequency: 5%-15% treated patients

Mortality rate: 5% to 10%

Cause: unknown (possibly related to amiodarone-mediated generation of free oxygen radicals in the lung)

Two types of amiodarone-pulmonary toxicity clinical presentations:

More common: Slow, insidious, progressive dyspnea, cough, weight loss, pulmonary infiltration (chest x-ray)

Acute onset: dyspnea, cough, arterial hypoxemia.

Anesthetic Implications: pulmonary

Suggested restriction of inspired oxygen concentration in patients receiving amiodarone and undergoing general anesthesia close level possible while retaining adequate systemic oxygenation

Postoperative pulmonary edema has been reported in patients treated with amiodarone chronically-- resembles acute onset form of amiodarone toxicity.

In patients with preexisting amiodarone-cause pulmonary damage are at increased risk for adult respiratory distress syndrome following surgery requiring cardiopulmonary bypass.

Cardiovascular Effects:

Prolongation of QT interval (ECG); increased incidence of ventricular tachyarrhythmias (including torsades de pointes)

Bradycardia (atropine-resistant)

Catecholamine responsiveness: diminished due to alpha and beta-receptor blocking activity

Hypotension; A-V block (following IV administration)

Anesthetic Implications: cardiovascular

With general anesthesia -- enhanced antiadrenergic action, presentation as:

A-V block, sinus arrest, decrease cardiac output, hypotension

Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal automaticity (e.g. lidocaine, halothane)

Consideration should be given for temporary ventricular pacemaker and sympathomimetic administration (e.g. isoproterenol) for patients taking amiodarone and scheduled undergo surgery.

Ocular and other Side Effects:

Corneal microdeposits: common;usually no visual impairment

Photosensitivity, rash: 10% frequency

Rare: cyanotic discoloration (slate-gray facial pigmentation)

Neurological:

Peripheral neuropathy; sleep disturbance, headache, tremor, some skeletal muscle weakness

Drug-drug interaction

Potent inhibitor of hepatic metabolism or renal elimination of many drugs.

Warfarin, quinidine gluconate (Quinaglute, Quinalan), procainamide (Procan SR, Pronestyl-SR) and digoxin (Lanoxin, Lanoxicaps) are examples of drugs which may require dosage reduction during amiodarone (Cordarone).

Amiodarone (Cordarone) displaces digoxin (Lanoxin, Lanoxicaps) from protein binding sites

Digoxin (Lanoxin, Lanoxicaps) levels may increase as much as 70%

Digoxin (Lanoxin, Lanoxicaps) dose should be decreased as much as 50% when amiodarone is administered concurrently

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343